PCOS is a common endocrine disorder characterized by hyperandrogenemia and oligomenorrhea/ amenorrhea. In addition to these reproductive features, PCOS is also associated with significant metabolic abnormalities including an increased incidence of obesity and insulin resistance and a 7x increased risk of developing type 2 diabetes mellitus (DM2). Genetic factors, lifestyle, and the prenatal environment are believed to contribute to the etiology of PCOS. Using family-based genetic studies, we have identified a PCOS susceptibility locus, D19S88, within intron 55 of FBN3, the gene encoding the extracellular matrix protein, fibrillin-3. In addition to their structural properties, members of the fibrillin gene family are also important in regulating the TGF-[unreadable] signaling cascade. Furthermore, the D19S884 disease-associated allele, A8, is associated with both the reproductive and metabolic features of PCOS in PCOS families. Based on these findings we hypothesize that variation in D19S884 alters FBN3 function and/or expression leading to perturbation in TGF-[unreadable] signaling and that this perturbation is important the development of insulin resistant states such as PCOS, DM2, and gestational diabetes (GDM). In this application, we address the role of variation at D19S884 and the TGF-[unreadable] signaling pathway in insulin resistant phenotypes with three specific aims. Aim 1 asks whether D19S884 is a susceptibility locus specifically for PCOS in women of European ancestry or whether it also contributes to other insulin resistant states (ie. pregnancy), is this effect the same in multiple ethnicities, and does D19S884 variation impact pregnancy outcome and fetal growth? These questions will be addressed with D19S884 association studies in the HAPO Study cohort, a multi-ethnic epidemiological study of 25,000 women and their babies collected to address glycemic control during pregnancy and its impact on pregnancy outcome. The second aim asks whether D19S884 allele status correlates with androgen levels in serum of pregnant mothers and/or neonates from the HAPO study. The third aim asks whether TGF-[unreadable] signaling is altered in PCOS. We will compare expression levels of ~60 genes in the TGF-[unreadable] signaling pathway in skin, muscle and fat tissues from women with PCOS and controls. These studies will result in a more global understanding of the role of D19S884 variation and TGF-[unreadable] signaling in PCOS, insulin resistance, and fetal growth - phenotypes that are of significant medical importance.